Oximes For Treatment Of Peripheral And Central Nervous System Exposure To Acetyl Cholinesterase Inhibitors

ABSTRACT

The present invention relates to non-charged oxime compounds which are acetyl cholinesterase (AChE) reactivators of inhibited AChE and which protect against organophosphate poisoning both peripherally and in the central nervous system. Also disclosed are pharmaceutical compositions and methods for preparing the reactivator compounds and associated intermediates.

GOVERNMENT RIGHTS CLAUSE

This invention was made with United States Government support underContract No. HDTRA1-10-C-0041 awarded by the Defense Threat ReductionAgency. The Government has certain rights in this invention.

FIELD OF THE INVENTION

The present invention relates to non-charged oxime compounds which areacetyl cholinesterase (AChE) reactivators of nerve-agent inhibited AChEand which protect against organophosphate poisoning both peripherallyand in the central nervous systems (CNS).

BACKGROUND

Acetyl cholinesterase (AChE) is an important and essential enzyme in thebody, which is responsible for the degradation or hydrolysis of acetylcholine, the neurotransmitter molecule responsible for synaptictransmission. Inhibition of AChE can cause a sharp increase in acetylcholine levels, causing overstimulation of the cholinergic system atboth central and peripheral sites, resulting in the visual toxic signscommonly referred to as cholinergic crisis. Organophorus agents, such aspesticides (paraoxon, methylparaoxon, etc.) and nerve agents (Sarin,Cyclosarin, Soman, Tabun, VX, etc) represent the bulk of the major AChEinhibitor threat agents. Historically, various compounds have beenproposed from the class of compounds that possess the N-alkylbis-quaternary pyridinium moiety as a charged species. As a chargedspecies, there may be diminished ability to penetrate the blood-brainbarrier and protect against organophosphate poisoning in the brain andcentral nervous system (CNS).

Therefore, the invention disclosed herein has identified certainnon-charged oxime based AChE reactivators with improved blood-brainbarrier penetration that may be effective at reactivation of nerveagent-inhibited AChE and protect against organophosphate poisoning bothperipherally and in the CNS.

SUMMARY

The present disclosure is directed at an acetyl cholinesterase (AChE)reactivator compound of the formula:

wherein

V is independently a hydrogen, alkyl (C1 to C5) groups, benzyl orsubstituted benzyl groups;

Z is independently an optionally substituted methylene or methine groupfrom 1 to 8 carbon atoms in length and wherein in the case of optionallysubstituted methylene or methine, Z can also be connected to R₁ to forma heterocyclic or bicyclic heteratom ring from 3 to 10 atoms;

R₁ can independently be H or optionally substituted alkyl (C1 to C7), orcan be connected to Z to form a heterocyclic or bicyclic heteratom ringfrom 3 to 10 atoms;

R₂ is independently H or optionally substituted alkyl (C1 to C7), benzylor optionally substituted benzyl, phenyl, optionally substituted phenyl,heterocyclic, heteroaryl and optionally substituted heterocyclic oroptionally substituted heteroaryl; and

X is independently H, cyano (CN) or COR, wherein said R group is alkyl(C1 to C3).

The present disclosure also relates to an acetyl cholinesterasereactivator compound of the formula:

wherein:

Q is independently a carbonyl (C═O) group or a bond between Y and theoxime group;

Y is independently an optionally substituted 5- or 6-memberedheterocycle or heteroaryl group;

Z is independently an oxygen, optionally substituted nitrogen oroptionally substituted methylene or methine group from 1 to 8 carbonatoms in length and wherein in the case of optionally nitrogen oroptionally substituted methylene or methine, Z can also be connected toR₁ to form a heterocyclic or bicyclic heteratom ring from 3 to 10 atoms;

R₁ can independently be H or optionally substituted alkyl (C1 to C7), orcan be connected to Z to form a heterocyclic or bicyclic heteratom ringfrom 3 to 10 atoms;

R₂ is independently H or optionally substituted alkyl (C1 to C7), benzylor optionally substituted benzyl, phenyl, optionally substituted phenyl,heterocyclic, heteroaryl and optionally substituted heterocyclic oroptionally substituted heteroaryl;

X is independently H, cyano (CN) or COR, wherein said R group is alkyl(C1 to C3).

The present disclosure also relates to a method comprising attenuatingthe effects on a mammal cause by the inhibition of AChE by administeringto said mammal an effective amount of a compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula I and/orFormula II noted above.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates two preferred methods for the preparation of AChEreactivator compounds disclosed herein.

FIG. 2 illustrates two additional preferred methods for preparation ofthe AChE reactivator compounds disclosed herein.

FIG. 3 illustrates a preferred method for the synthesis of theintermediate 12 identified in FIG. 2.

FIG. 4 illustrates a preferred method for the synthesis of compound 13prepared in FIG. 2.

FIG. 5 illustrates a preferred method for the synthesis of the compoundof compound 4 in FIG. 1.

DETAILED DESCRIPTION

It is to be understood that the invention is not limited in itsapplication to the details of construction and the arrangement ofcomponents set forth in the following description or illustrated in thedrawings. The invention is capable of other embodiments and of beingpracticed or of being carried out in various ways. Also, it is to beunderstood that the phraseology and terminology used herein is for thepurpose of description and should not be regarded as limiting. The useof “including,” “comprising,” or “having” and variations thereof hereinis meant to encompass the items listed thereafter and equivalentsthereof as well as additional items.

The compounds of the present invention are directed to pharmaceuticalcountermeasures or antidote compositions for treating disorders orconditions associated with exposure to AChE inhibitors such asorganophosphate pesticides and nerve agents. The compounds of thepresent invention may therefore serve as reactivators of both nativeand/or organophosphate-inhibited acetyl cholinesterase (AChE). Referenceto a reactivator may be understood as that situation where, e.g., enzymedephosphorylation occurs to generate the active enzyme (AChE) and isrelatively faster than oxime dephosphorylation, which generates thephosphorylated enzyme.

Accordingly, the compounds of the present invention serve asreactivators of nerve agent organophosphate-inhibited human and/ormammalian acetyl cholinesterase (AChE), including AChE inhibited bySarin, Cyclosarin (GF), Tabun, Soman, VX and other structurally relatedorganophosphate nerve agents.

More particularly, the reactivator compounds of the present inventioninclude compounds of Formula I below:

wherein:

V is independently a hydrogen, alkyl (C1 to C5) groups, benzyl orsubstituted benzyl groups;

Z is independently an optionally substituted methylene or methine groupfrom 1 to 8 carbon atoms in length. In the case of optionallysubstituted methylene or methine, Z can also be connected to R₁ to forma heterocyclic or bicyclic heteratom ring from 3 to 10 atoms;

R₁ can independently be H or optionally substituted alkyl (C1 to C7), orcan be connected to Z to form a heterocyclic or bicyclic heteratom ringfrom 3 to 10 atoms;

R₂ is independently H or optionally substituted alkyl (C1 to C7), benzylor optionally substituted benzyl, phenyl, optionally substituted phenyl,heterocyclic, heteroaryl and optionally substituted heterocyclic oroptionally substituted heteroaryl;

X is independently H, cyano (CN) or COR, wherein said R group is alkyl(C1 to C3); and

wherein the oxime moiety can exist as either the E or Z isomer form. Inaddition, the above Formula I may be present in the form of apharmaceutically acceptable salt.

The present invention is also directed at reactivators having thestructure of Formula II:

wherein:

Q is independently a carbonyl (C═O) group or a bond between Y and theoxime group;

Y is also independently an optionally substituted 5- or 6-memberedheterocycle or heteroaryl group such as oxazole, triazole, imidazole,oxadiazole, pyridine, pyrimidine or pyrazine;

Z is independently an oxygen, optionally substituted nitrogen oroptionally substituted methylene or methine group from 1 to 8 carbonatoms in length. In the case of optionally nitrogen or optionallysubstituted methylene or methine, Z can also be connected to R₁ to forma heterocyclic or bicyclic heteratom ring from 3 to 10 atoms;

R₁ can independently be H or optionally substituted alkyl (C1 to C7), orcan be connected to Z to form a heterocyclic or bicyclic heteratom ringfrom 3 to 10 atoms;

R₂ is independently H or optionally substituted alkyl (C1 to C7), benzylor optionally substituted benzyl, phenyl, optionally substituted phenyl,heterocyclic, heteroaryl and optionally substituted heterocyclic oroptionally substituted heteroaryl;

X is independently H, cyano (CN) or COR, wherein said R group is alkyl(C1 to C3); and

wherein the oxime moiety can exist as either the E or Z isomer form. Inaddition, the above Formula II may be present in the form of apharmaceutically acceptable salt.

It may be understood that with respect to the oxime moiety, the Zdesignation is that situation where the two groups of higher priority(according to the Cahn-Ingold-Prelog priority rules) are on the sameside of the double bond. If the two groups of higher priority are onopposite sides of the double bond, it is designated as the E isomer. Inrelated context, the compounds of Formula I and II may also have opticalcenters and therefore may occur in different enantiomericconfigurations. Accordingly, the general formulas identified aboveshould be understood to preferably include all enantiomers,diastereomers and other stereoisomers of the defined compounds as wellas racemic and other mixtures thereof.

As may be appreciated, the compounds herein are preferably non-charged,which may be understood as the feature where the compound itself asidentified in the general formula above does not include a charged atomor functional group. As noted, this may then facilitate blood-brainbarrier penetration. However, as noted, pharmaceutically acceptablesalts of the compounds of Formula I and II may also be employed andinclude the acid addition and base salts thereof. The phrase“pharmaceutically acceptable”, as used in connection with compositionsof the invention, refers to molecular entities and other ingredients ofsuch compositions that are physiologically tolerable and do nottypically produce untoward reactions when administered to a mammal(e.g., human). Preferably, as used herein, the term “pharmaceuticallyacceptable” means approved by a regulatory agency of the Federal or astate government or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in mammals, and more particularly inhumans.

Some examples of pharmaceutically acceptable salt forms include, but arenot limited to: acetate, adipate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, citrate, formate,fumarate, gluconate, glucuronate, hexafluorophosphate,hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,lactate, malate, maleate, malonate, mandelates, mesylate,methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, oxalate,palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate,pyroglutamate, salicylate, saccharate, stearate, succinate, sulfonate,stannate, tartrate, tosylate, and trifluoroacetate salts.

Suitable base salts are preferably formed from bases which formnon-toxic salts. Some examples include, but are not limited to, thealuminium, calcium, choline, diethylamine, diolamine, glycine, lysine,magnesium, meglumine, olamine, potassium, sodium, and zinc salts.

The compounds of the present invention may be used as part of acombination therapy, including their administration as separate entitiesor combined in a single delivery system. The combination therapies mayinclude, but are not limited to combination with an AChE inhibitor suchas atropine and/or an anticonvulsant such as diazepam or midazelam.

The compounds of this invention may be preferably administered viaeither the oral, parenteral (such as subcutaneous, intraveneous,intramuscular, intrasternal and infusion techniques), intranasal ortopical routes to mammals. In general, these compounds are mostdesirably administered to humans in doses ranging from about 1.0 mg toabout 2000 mg per day, although variations will necessarily occurdepending upon the weight and condition of the subject being treated andthe particular route of administration chosen.

The compounds of the present invention may be administered alone or incombination with pharmaceutically acceptable carriers or diluents byeither of the above routes previously indicated, and such administrationmay be carried out in single or multiple doses. More particularly, thereactivator compounds of the invention may be administered in a widevariety of different dosage forms, i.e., they may be combined withvarious pharmaceutically acceptable inert carriers in the form oftablets, capsules, lozenges, troches, hard candies, powders, sprays,creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, organic suspensions, injectablesolutions, injectable suspensions, elixirs, syrups, and the like. Suchcarriers may include solid diluents or fillers, sterile aqueous mediaand various non-toxic organic solvents, etc. Moreover, oralpharmaceutical compositions can be suitably sweetened and/or flavored.In general, the therapeutically effective compounds of this inventionare present in such dosage forms at concentration levels ranging about5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch, together with granulation binders likepolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are preferred for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in gelatine capsules;preferred materials in this connection also include lactose or milksugar as well as high molecular weight polyethylene glycols. Whenaqueous suspensions and/or elixirs are desired for oral administration,the active ingredient may be combined with various sweetening orflavoring agents, coloring matter or dyes, and, if so desired,emulsifying and/or suspending agents as well, together with suchdiluents as water, ethanol, propylene glycol, glycerin and various likecombinations thereof.

For parenteral administration, solutions or suspensions of a compound ofthe present invention in either sesame or peanut oil, cotton seed oil orin aqueous propylene glycol may be employed. The aqueous solutionsshould be suitably buffered (preferably pH>8) if necessary and theliquid diluents first rendered isotonic. These aqueous solutions arepreferred for intravenous injection purposes. The oily solutions arepreferred for intra-articular, intra-muscular and subcutaneous injectionpurposes. The preparation of all these solutions under sterileconditions is readily accomplished by standard pharmaceutical techniqueswell-known to those skilled in the art. Additionally, it is alsopossible to administer the compounds of the present invention topicallywhen treating inflammatory conditions of the skin and this maypreferably be done by way of creams, jellies, gels, pastes, ointmentsand the like, in accordance with standard pharmaceutical practice.

The reactivator compounds of the present invention may exist in bothunsolvated and solvated forms. The term ‘solvate’ is used herein todescribe a molecular complex comprising the compound of the inventionand an amount of one or more pharmaceutically acceptable solventmolecules, such as water.

The reactivator compounds of the present invention may also includeisotopically labeled compounds, which are identical to those recited inthe above referenced formula, but for the fact that one or more atomsare replaced by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number usually found in nature therebyallowing for improved detection and/or tracking of the compound.Examples of isotopes suitable for inclusion in the compounds of theinvention include, but are not limited to, isotopes of hydrogen, such as²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl,fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P,and sulphur, such as ³⁵S.

Certain isotopically-labelled reactivator compounds herein, for example,those incorporating a radioactive isotope, may be preferred in drugand/or substrate tissue distribution studies. The radioactive isotopestritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly preferredfor this purpose in view of their relative ease of incorporation andready means of detection. Substitution with heavier isotopes such asdeuterium, i.e. ²H, may afford certain therapeutic advantages resultingfrom greater metabolic stability, for example, increased in vivohalf-life or reduced dosage requirements, and hence may be preferred insome circumstances. Substitution with positron emitting isotopes, suchas ¹¹C, ¹⁸F, ¹⁵O, and ¹³N, may be useful in Positron Emission Topography(PET) studies for examining substrate receptor occupancy.Isotopically-labeled reactivator compounds herein may generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the accompanying examplesand preparations using an appropriate isotopically-labeled reagent inplace of the non-labeled reagent previously employed.

Reactivator compounds of Formula I herein were assessed for affinity andreactivation of nerve agent-inhibited recombinant human AChE.Reactivation studies were conducted with commercially obtainedrecombinant human AChE and assayed by a robotic spectrophotometric assayusing acetylthiocholine as substrate at pH 7.4 and 25° C. via theprocedure established by Ellman (Biochem Pharmacol 1961, 7, 88-95). Thetime-course of reactivation of nerve agent-inhibited AChE was determinedby adding various concentrations of reactivator compounds of theabove-referenced formula to agent-inhibited AChE. Samples of thecompound/inhibited AChE mixture were removed at sequential times tomeasure the compound-induced recovery of AChE activity. The time-courseof AChE reactivation at each compound concentration [OX] was analyzedkinetically as a pseudo first-order reaction. The observed first-orderreaction constant (k_(obs)) was fitted to the Michaelis-Menten function:

k _(obs) =kr[OX]/(KD+[OX])

where kr is the maximal first-order reactivation rate constant for thereactivator compound considered and 1/KD is its affinity for AChE. Invitro reactivation studies were conducted against AChE that has beeninhibited with the nerve agent GF (cyclosarin). Reactivator compounds ofthe herein referenced general formula within this invention showed10-80% reactivation of GF-inhibited human AChE at concentrations from500 nM to 1 mM and time points from 8 to 240 minutes.

The reactivator compounds of Formula I may preferably be prepared by themethods described below, together with synthetic methods known in theart of organic chemistry, or modifications and derivatisations that arefamiliar to those of ordinary skill in the art. During any of thefollowing synthetic sequences it may be preferred and/or desirable toprotect sensitive or reactive groups on any of the molecules concerned.This can be achieved by means of conventional protecting groups, such asthose described in T. W. Greene, Protective Groups in Organic Chemistry,John Wiley & Sons, 1981; and T. W. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Chemistry, John Wiley & Sons, 1991, which are herebyincorporated by reference.

Reactivator compounds of Formula I and/or their pharmaceuticallyacceptable salts may preferably be prepared according to the followingreaction Schemes I and II as discussed herein and respectivelyillustrated in FIGS. 1 and 2. Isolation and purification of the productsmay be accomplished by standard procedures, which are known to a chemistof ordinary skill. The following schemes and discussion are exemplary ofthe processes for making compounds of general formula I. It is to beunderstood, however, that the synthetic scheme, as fully describedherein, is not intended to be limited by the details of the followingexamples.

FIG. 1 illustrates two preferred methods for the preparation ofreactivator compounds having the basic structure of the above referencedgeneral formula, where Z, R₁ and R₂ are defined as above. Referring toFIG. 1, compounds of formula I can be purchased or prepared usingsynthetic methods known in the art of organic chemistry, ormodifications and derivatisations that are familiar to those of ordinaryskill in the art. Referring to FIG. 1, an amine of formula I can betreated with a tartrate ester such as compound 2 in an alcoholic solventsuch as ethanol or methanol, at temperatures ranging from roomtemperature to 75° C., preferably at or around 45° C., to provide thedimeric amide of general formula 3. Compounds of formula 3 can then betreated under acidic sodium periodate conditions in solvents such asalcohol or water, preferably ethanol and water, to provide theintermediate amide-aldehyde (not depicted), which can then beimmediately reacted with hydroxylamine hydrochloride, alone or in thepresence of a tertiary amine base, such as triethylamine, to produce thedesired compounds of formula 4. An alternative method for thepreparation of compounds of formula 4 is also described in FIG. 1.Compounds of formula I can be treated with the gloxylate oximes, such asethyl 2-(hydroxyimino)acetate 5 in a suitable solvent such as ethanol,DMF or acetonitrile, or reacted neat with the compound of formula I, attemperatures ranging from room temperature to 150° C., preferably atabout 80° C., to produce the desired amide-oxime compounds of formula 4.

FIG. 2 illustrates another preferred method for the preparation ofreactivator compounds having the general formula above, where Y, Z, R₁and R₂ are defined as above, Y is an oxygen or nitrogen atom ofappropriate substitution, W is independently CH (methine) or N(nitrogen) and ‘Hal’ represents halogen groups, such as fluoride,chloride, bromide or iodide. Referring to FIG. 2, an alcohol or amine offormula 6 can be reacted with a di-halogenated heterocyclic compound offormula 7 to form the desired heteroaryl ether or heteroaryl amine offormula 8. Conditions for this reaction include the use of a suitablebase such as sodium hydride (NaH) or potassium tert-butoxide (KOtBu) insolvents such as tetrahydrofuran (THF) or diethyl ether, at temperaturesranging from room temperature to 100° C., preferably around 60° C., toprovide the desired compounds of formula 8. Treatment of compounds offormula 8 with a suitable Grignard reagent or organolithium reagent,such as Isopropyl magnesium chloride (iPrMgCl) or n-butyl lithium(n-BuLi) and dimethylformamide, in solvents such as toluene, THF orether, at temperatures ranging from −100° C. to room temperature,provides the corresponding aldehyde (not depicted), which can then beimmediately reacted with hydroxylamine hydrochloride, in a solvent suchas ethanol or dichloromethane, alone or in the presence of a tertiaryamine base, such as triethylamine, to produce the desired oximecompounds of formula 9.

As also illustrated in FIG. 2, ketone compounds of formula 12 can alsobe prepared from the compounds of formula 8 via two methods. Treatmentof compounds of formula 8 with a suitable Grignard reagent ororganolithium reagent, such as Isopropyl magnesium chloride (iPrMgCl) orn-butyl lithium (n-BuLi) and the Weinreb amide 10, in solvents such astoluene, THF or ether, at temperatures ranging from −100° C. to roomtemperature, provides the corresponding ketone compounds of formula 12.Alternatively, compounds of formula 8 can be coupled with the vinylstannane reagent 11, utilizing a suitable catalyst such astetrakistriphenylphosphine palladium (0), to produce the correspondingvinyl ether (not depicted), which can be hydrolyzed with HCl to producethe ketone compounds of formula 12. Ketone compounds of formula 12 canbe reacted under a variety of conditions to produce the desiredketo-oxime compounds of formula 13. Suitable conditions for thistransformation include trimethylsilyl chloride and nitrosyl chloride,potassium tert-butoxide and tert-butyl nitrite (tBuNO₂) or isoamylnitrite.

As illustrated in FIG. 3, a method is identified for the synthesis ofthe intermediate 12 prepared above in FIG. 2. Referring to FIG. 3, analcohol or amine of general formula 6 can be reacted with ahalogenated-methyl ketone heterocyclic compound of general formula 14 toform the desired heteroaryl ether or heteroaryl amine of general formula12. Conditions for this reaction include the use of a suitable base suchas sodium hydride (NaH) or potassium tert-butoxide (KOtBu) in solventssuch as tetrahydrofuran (THF) or diethyl ether, at temperatures rangingfrom room temperature to 100° C., preferably around 60° C., to providethe desired compounds of general formula 12. Other conditions for thistransformation involve the use of a suitable palladium catalyst, such asPd(OAc)₂ and a ligand, in solvent such as DMF or THF. Intermediate 12can be taken on to the desired compounds of Formula II as describedabove in FIG. 2.

FIG. 4 identifies another method for the synthesis of the compound ofgeneral formula 13, prepared above in FIG. 2. Referring to FIG. 4, ahalogenated heteroaryl ketone of general formula 14 can be reacted undera variety of conditions to produce the desired keto-oxime intermediateof general formula 15. Suitable conditions for this transformationinclude trimethylsilyl chloride and nitrosyl chloride, potassiumtert-butoxide and tert-butyl nitrite (tBuNO₂) or isoamyl nitrite.Compound 15 can then be reacted with the alcohol or amine of generalformula 6, under similar conditions to those described above forcompound 12 above (Scheme III) to provide the desired compounds ofgeneral formula 13.

FIG. 5 identifies yet another method for the synthesis of the compoundof general formula 4, prepared above in FIG. 1. Referring to FIG. 5, anamine of general formula I can be treated with methyl2,2-dimethyl-1,3-dioxolane-4-carboxylate, 16 neat at temperaturesranging from room temperature to 130° C., preferably at or around 120°C., to provide the amide of general formula 17. Compounds of formula 17can then be treated under HCl/THF or other suitable acidic conditions todeprotect the acetonide moiety and provide the desired diol (notdepicted). Treatment of the diol with acidic sodium periodate conditionsin solvents such as alcohol or water, preferably ethanol and water, toprovide the intermediate amide-aldehyde (not depicted), which can thenbe immediately reacted with hydroxylamine hydrochloride, alone or in thepresence of a tertiary amine base, such as triethylamine, to produce thedesired compounds of general formula 4.

Finally, compounds of Formula I and II prepared in FIGS. 1-5 may have apharmaceutically acceptable salt form prepared under standard conditionsby one skilled in the art. As a representative example, amide-oxime andketo-oxime compounds of formulas 4, 9 or 13 (FIGS. 1 and 2) can bedissolved in a suitable solvent such as methanol, ethanol,dichloromethane, ethyl acetate or isopropyl acetate and treated with asuitable acid, such as an anhydrous solution of HCl in ether, to producethe corresponding hydrochloric acid salt form.

The following examples were prepared according to the schemes identifiedin FIGS. 1-5 and the description provided herein.

Example Structure IUPAC Name Example 1 

N-(2-(diethylamino)ethyl)-2- (hydroxyimino)acetamide hydrochlorideExample 2 

N-((1-benzylpiperidin-4-yl)methyl)-2- (hydroxyimino)acetamidehydrochloride Example 3 

N-(1-benzylpiperidin-4-yl)-2- (hydroxyimino)acetamide hydrochlorideExample 4 

6-((1-benzylpiperidin-4- yl)methoxy)nicotinaldehyde oxime hydrochlorideExample 5 

2-(hydroxyimino)-N-(3-(1,2,3,4- tetrahydroacridin-9-ylamino)propyl)acetamide hydrochloride Example 6 

2-(hydroxyimino)-N-(4-(1,2,3,4- tetrahydroacidin-9-ylamino)butyl)acetamide hydrochloride Example 7 

2-(hydroxyimino)-N-(6-(1,2,3,4- tetrahydroacridin-9-ylamino)hexyl)acetamide hydrochloride Example 8 

2-(hydroxyimino)-N-(7-(1,2,3,4- tetrahydroacridin-9-ylamino)heptyl)acetamide hydrochloride Example 9 

2-(hydroxyimino)-N-(5-(1,2,3,4- tetrahydroacridin-9-ylamino)pentyl)acetamide hydrochloride Example 10

2-(2-((1-benzylpiperidin-4- yl)methoxy)pyrimidin-5-yl)-2-oxoacetaldehyde oxime hydrochloride Example 11

2-(6-((1-benzylpiperidin-4- yl)methoxy)pyidin-3-yl)-2- oxoacetaldehydeoxime hydrochloride Example 12

2-((1-benzylpiperidin-4- yl)methoxy)pyrimidine-5-carbaldehyde oximehydrochloride Example 13

2-(6-(3- (diethylamino)propoxy)pyridin-3-yl)-2- oxoacetaldehyde oximehydrochloride Example 14

6-(3- (diethylamino)propoxy)nicotinaldehyde oxime hydrochloride Example15

N-(1-benzylpiperidin-4-yl)-2- (hydroxyimino)-3-oxobutanamidehydrochloride Example 16

2-(1-benzylpiperidin-4-ylamino)-N- hydroxy-2-oxoacetimidoyl cyanidehydrochloride Example 17

N-((1-benzylpiperidin-4-yl)methyl)-2- (hydroxyimino)-3-oxobutanamidehydrochloride Example 18

2-((1-benzylpiperidin-4- yl)methylamino)-N-hydroxy-2- oxoacetimidoylcyanide hydrochloride Example 19

N-benzyl-2-(hydroxyimino)-N-(5- (1,2,3,4-tetrahydroacridin-9-ylamino)pentyl)acetamide hydrochloride

MDR/MDCK Assay Description and Data

Compounds within this invention were screened in the MDR/MDCK assay,which has been found to be a reasonable in vitro predictor for effluxactivity associated with the blood-brain barrier. See, Wang, Q. et al,Evaluation of the MDR-MDCK Cell Line As a Permeability Screen For TheBlood Brain Barrier, Int. J. Pharm. 2005, 288(2) 349-359. The assay is abidirectional assay in a transwell format system, assessing thepermeability of compounds across a Madin Darby canine kidney cell linetransfected with human MDR-1 gene. Efflux is assessed based on ratiosfrom the basolateral and apical sides of the chamber.

The MDR/MDCK data for select compounds is highlighted in Table I below.As can be seen, the compounds herein demonstrate a range of brainpenetration classifications.

TABLE I Papp Brain (×10⁻⁶ cm/s) Penetration Compound A-B B-A EffluxClassification N-((1-benzylpiperidin-4-yl)methyl)-2- 3.19 19.8 6.2Moderate (hydroxyimino)acetamide hydrochlorideN-(2-(diethylamino)ethyl)-2- <0.51 <0.67 ND Low (hydroxyimino)acetamidehydrochloride 2-(hydroxyimino)-N-(3-(1,2,3,4-tetrahydroacridin-9- 0.214.37 21 Low ylamino)propyl)acetamide hydrochloride2-(hydroxyimino)-N-(5-(1,2,3,4-tetrahydroacridin-9- 0.3 7.92 26 Lowylamino)pentyl)acetamide hydrochloride2-(2-((1-benzylpiperidin-4-yl)methoxy)pyrimidin-5- 9.2 12.3 1.3 Highyl)-2-oxoacetaldehyde oxime hydrochloride2-(6-((1-benzylpiperidin-4-yl)methoxy)pyridin-3-yl)- 13.5 9.54 0.7 High2-oxoacetaldehyde oxime hydrochloride2-((1-benzylpiperidin-4-yl)methylamino)-N-hydroxy- 0.07 0.44 5.9 Low2-oxoacetimidoyl cyanide hydrochlorideN-((1-benzylpiperidin-4-yl)methyl)-2-(hydroxyimino)- 17.4 21.3 1.2 High3-oxobutanamide hydrochloride2-(6-(3-(diethylamino)propoxy)pyridin-3-yl)-2- 6.46 18.6 2.9 Highoxoacetaldehyde oxime hydrochloride 1,1′-methylenebis(4- <0.57 <0.57 NDLow (hydroxyimino)methyl)pyridinium)methanesulfonate (MMB4 DMS-Controlbis-pyridinium)

1. An acetyl cholinesterase reactivator compound of the formula:

wherein V is independently a hydrogen, alkyl (C1 to C5) groups, benzylor substituted benzyl groups; Z is independently an optionallysubstituted methylene or methine group from 1 to 8 carbon atoms inlength and wherein in the case of optionally substituted methylene ormethine, Z can also be connected to R₁ to form a heterocyclic orbicyclic heteratom ring from 3 to 10 atoms; R₁ can independently be H oroptionally substituted alkyl (C1 to C7), or can be connected to Z toform a heterocyclic or bicyclic heteratom ring from 3 to 10 atoms; R₂ isindependently H or optionally substituted alkyl (C1 to C7), benzyl oroptionally substituted benzyl, phenyl, optionally substituted phenyl,heterocyclic, heteroaryl and optionally substituted heterocyclic oroptionally substituted heteroaryl; and X is independently H, cyano (CN)or COR, wherein said R group is alkyl (C1 to C3).
 2. The acetylcholinesterase reactivator compound of claim 1 wherein the reactivatoris present as the E or Z isomer with respect to the oxime moiety.
 3. Theacetyl cholinesterase reactivator compound of claim 1 wherein saidcompound comprises a pharmaceutically acceptable salt comprising an acidaddition salt or base addition salt.
 4. The acetyl cholinesterasereactivator compound of claim 3 wherein said pharmaceutically acceptablesalt comprises one or more of the following salts: acetate, adipate,aspartate, benzoate, besylate, bicarbonate/carbonate,bisulphate/sulphate, borate, citrate, formate, fumarate, gluconate,glucuronate, hexafluorophosphate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, lactate, malate, maleate,malonate, mandelates, mesylate, methylsulphate, naphthylate,2-napsylate, nicotinate, nitrate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate,salicylate, saccharate, stearate, succinate, sulfonate, stannate,tartrate, tosylate, and trifluoroacetate salts.
 5. The acetylcholinesterase reactivator compound of claim 3 wherein saidpharmaceutically acceptable salt comprises a base salt comprising one ormore of the following: aluminium, calcium, choline, diethylamine,diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium,sodium, and zinc.
 6. The acetyl cholinesterase reactivator compound ofclaim 1 wherein said compound is isotropically labeled.
 7. The acetylcholinesterase reactivator compound of claim 6 wherein said isotropiclabeling comprises labeling with one or more of the following: ²H, ³H,¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, and³⁵S.
 8. A method comprising attenuating the effects on a mammal causedby the inhibition of AChE by administering to said mammal an effectiveamount of a compound, or a pharmaceutically acceptable salt thereof,having the following structure:

wherein V is independently a hydrogen, alkyl (C1 to C5) groups, benzylor substituted benzyl groups; Z is independently an optionallysubstituted methylene or methine group from 1 to 8 carbon atoms inlength and wherein in the case of optionally substituted methylene ormethine, Z can also be connected to R₁ to form a heterocyclic orbicyclic heteratom ring from 3 to 10 atoms; R₁ can independently be H oroptionally substituted alkyl (C1 to C7), or can be connected to Z toform a heterocyclic or bicyclic heteratom ring from 3 to 10 atoms; R₂ isindependently H or optionally substituted alkyl (C1 to C7), benzyl oroptionally substituted benzyl, phenyl, optionally substituted phenyl,heterocyclic, heteroaryl and optionally substituted heterocyclic oroptionally substituted heteroaryl; and X is independently H, cyano (CN)or COR, wherein said R group is alkyl (C1 to C3).
 9. The method of claim8 wherein said compound is administered at a dosage of 1.0 mg to 2000 mgper day.
 10. The method of claim 8 wherein said compound is administeredprior to exposure to a chemical agent wherein said agent inhibits AChE.11. The method of claim 8 wherein said compound is administered afterexposure to a chemical agent wherein said agent inhibits AChE.
 12. Themethod of claim 1 further comprising administering an AChE inhibitor.13. An acetyl cholinesterase reactivator compound of the formula:

wherein: Q is independently a carbonyl (C═O) group or a bond between Yand the oxime group; Y is independently an optionally substituted 5- or6-membered heterocycle or heteroaryl group; Z is independently anoxygen, optionally substituted nitrogen or optionally substitutedmethylene or methine group from 1 to 8 carbon atoms in length andwherein in the case of optionally nitrogen or optionally substitutedmethylene or methine, Z can also be connected to R₁ to form aheterocyclic or bicyclic heteratom ring from 3 to 10 atoms; R₁ canindependently be H or optionally substituted alkyl (C1 to C7), or can beconnected to Z to form a heterocyclic or bicyclic heteratom ring from 3to 10 atoms; R₂ is independently H or optionally substituted alkyl (C1to C7), benzyl or optionally substituted benzyl, phenyl, optionallysubstituted phenyl, heterocyclic, heteroaryl and optionally substitutedheterocyclic or optionally substituted heteroaryl; X is independently H,cyano (CN) or COR, wherein said R group is alkyl (C1 to C3).
 14. Theacetyl cholinesterase reactivator compound of claim 13 wherein thereactivator is present as the E or Z isomer with respect to the oximemoiety.
 15. The acetyl cholinesterase reactivator compound of claim 13wherein said compound comprises a pharmaceutically acceptable saltcomprising an acid addition salt or base addition salt.
 16. The acetylcholinesterase reactivator compound of claim 15 wherein saidpharmaceutically acceptable salt comprises one or more of the followingsalts: acetate, adipate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, citrate, formate,fumarate, gluconate, glucuronate, hexafluorophosphate,hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,lactate, malate, maleate, malonate, mandelates, mesylate,methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, oxalate,palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate,pyroglutamate, salicylate, saccharate, stearate, succinate, sulfonate,stannate, tartrate, tosylate, and trifluoroacetate salts.
 17. The acetylcholinesterase reactivator compound of claim 16 wherein saidpharmaceutically acceptable salt comprises a base salt comprising one ormore of the following: aluminium, calcium, choline, diethylamine,diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium,sodium, and zinc.
 18. The acetyl cholinesterase reactivator compound ofclaim 13 wherein said compound is isotropically labeled.
 19. The acetylcholinesterase reactivator compound of claim 18 wherein said isotropiclabeling comprises labeling with one or more of the following: ²H, ³H,¹¹C, ¹³C, ¹⁴C, ³⁶CL, ¹⁸F, ¹²³I, ¹²⁵ _(I,) ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P,and ³⁵S.
 20. A method comprising attenuating the effects on a mammalcause by the inhibition of AChE by administering to said mammal aneffective amount of a compound, or a pharmaceutically acceptable saltthereof, having the following structure:

wherein: Q is independently a carbonyl (C═O) group or a bond between Yand the oxime group; Y is independently an optionally substituted 5- or6-membered heterocycle or heteroaryl group; Z is independently anoxygen, optionally substituted nitrogen or optionally substitutedmethylene or methine group from 1 to 8 carbon atoms in length andwherein in the case of optionally nitrogen or optionally substitutedmethylene or methine, Z can also be connected to R₁ to form aheterocyclic or bicyclic heteratom ring from 3 to 10 atoms; R₁ canindependently be H or optionally substituted alkyl (C1 to C7), or can beconnected to Z to form a heterocyclic or bicyclic heteratom ring from 3to 10 atoms; R₂ is independently H or optionally substituted alkyl (C1to C7), benzyl or optionally substituted benzyl, phenyl, optionallysubstituted phenyl, heterocyclic, heteroaryl and optionally substitutedheterocyclic or optionally substituted heteroaryl; X is independently H,cyano (CN) or COR, wherein said R group is alkyl (C1 to C3).
 21. Themethod of claim 20 wherein said compound is administered at a dosage of1.0 mg to 2000 mg per day.
 22. The method of claim 20 wherein saidcompound is administered prior to exposure to a chemical agent whereinsaid agent inhibits AChE.
 23. The method of claim 20 wherein saidcompound is administered after exposure to a chemical agent wherein saidagent inhibits AChE.
 24. The method of claim 20 further comprisingadministering an AChE inhibitor.